Cancer is the second leading cause of death in the United States. It presents complex challenges for the development of new therapies. Cancer is characterized by the abnormal growth of malignant cells that have undergone a series of genetic changes that lead to growth of tumor mass and metastatic properties.
Transducin β-like protein 1 (TBL1) family of proteins has been shown to be involved in the transcriptional activator by acting as a co-regulator exchange factor. The TBL1 family is composed of TBL1X, TBL1Y and TBLR1 proteins. These proteins are components of the SMRT-nuclear receptor/co-repressor (N-CoR) complex where they act to exchange the co-repressors and co-activators on the complex. SMRT and NCoR are large co-repressor proteins that are involved in the transcriptional repression by many different nuclear receptors. TBL1 family of proteins forms a reversible complex with NCoR/SMRT to act as a transcriptional activator for nuclear receptors.
Beta-catenin (β-catenin) is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. β-catenin also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete.
Wnt/β-catenin pathway has been shown to play a role in cancer. Recent studies have shown that TBL1 is able to bind to β-catenin and recruit the complex to Wnt responsive promoters to activate specific transcriptional program. It has also been shown that TBL1 is required for β-catenin to actively transcribe target genes. Further, TBL1 appears to protect β-catenin from ubiquitination (a post-translational modification by certain enzymes) and degradation. However, the mechanism of the interaction between TBL1 and β-catenin is unknown.
Aberrant β-catenin signaling plays a important role in tumorigenesis. In particular, colorectal cancer is estimated to have greater than 80% mutations in the β-catenin pathway, leading to unregulated oncogenic signaling. Aberrant β-catenin signaling has been shown to be involved in various cancer types, including melanoma, breast, lung, liver, gastric, myeloma, and acute myeloid leukemia (AML). Further, aberrant Wnt/β-catenin signaling has been found in a large number of other disorders, including osteoporosis, osteoarthritis, polycystic kidney disease, diabetes, schizophrenia, vascular disease, cardiac disease, hyperproliferative disorders, and neurodegenerative diseases. Myeloproliferative neoplasms (MPNs) are a closely related group of hematological malignancies in which the bone marrow cells that produce the body's blood cells develop and function abnormally. The three main myeloproliferative neoplasms are Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). A gene mutation in JAK2 is present in most PV patients and 50% of ET and PMF patients. The beta catenin pathway is activated in MPN in many cases and required for survival of these cells.
Chronic Myeloid Leukemia is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood that contain the “Philadelphia chromosome”, where a piece of chromosome 9 and a piece of chromosome 22 break off and trade places to form the bcr-abl fusion gene. CML has activation of several other oncogenic pathways including the beta catenin pathway which is required for CML cell growth.
Accordingly, there is a need for agents that are able interrupt the Wnt/β-catenin pathway and inhibit the deregulated activity of this pathway for the treatment, diagnosis and prevention of β-catenin pathway-related disorders and diseases.